Intermittent Hypoxia Studies
Throughout the years, the American SIDS Institute has been involved in projects to learn more about the underlying medical vulnerabilities that make an infant more likely to die suddenly. Several studies have focused on infants’ abilities to control heart rate and breathing and on what causes these mechanisms to sometimes break down. Preterm infants commonly have breathing instability, and this can teach us a lot about the resulting problems and successful treatment. Therefore, we often partner with neonatologists to study infants in the NICU (neonatal intensive care unit).
A recent series of studies have looked at intermittent hypoxia. This occurs when an infant’s irregular breathing patterns cause dips in his oxygen levels. These up and down fluctuations are not clinically apparent and can only be measured by continuous recordings of oxygen blood levels using pulse oximeters. I intermittent hypoxia is known to be pro-inflammatory and appears to have long term adverse consequences, including neuro-developmental changes. Intermittent hypoxia is also very common in children and adults with sleep apnea and there is evidence that even modest amounts of intermittent hypoxia lead to impairments in cognitive performance. Caffeine is commonly used in the early weeks of care of premature infants to treat symptoms related to immature breathing regulation, which also reduces the frequency of intermittent hypoxia.
Phase 1 – Intermittent Hypoxia and Extended Caffeine Treatment
Under the direction of one of our board members, Dr. Carl Hunt, who is at Uniformed Services University of the Health Sciences (USUHS), we have completed a study of preterm babies in neonatal intensive care units (NICUs). Participating in the study were 16 hospital NICUs, a data coordinating center at Boston University, USUHS and the American SIDS Institute. The Institute provided funding assistance and our executive director, Dr. Betty McEntire, served as the project director. The results of this study were published in the March issue of JAMA Pediatrics.
For this first study, we hypothesized that intermittent hypoxia is still occurring even after the immature breathing was no longer apparent, and that extended caffeine treatment could reduce intermittent hypoxia episodes. We randomly assigned caffeine-treated infants born at less than 32 weeks’ gestation to receive extended treatment with caffeine at a usual NICU dose or to usual care (n=53) once they had reached 34 to 37 weeks’ postmenstrual age (PMA). Infants underwent continuous oxygen saturation (pulse oximeter) monitoring until they had been home for at least one week and had reached at least 40 weeks’ PMA. At 35 weeks’ PMA, control infants spent an average of 106 seconds per hour (s/h) with oxygen saturation (SaO2) levels below 90%; at 36 weeks’ PMA, time spent below 90% SaO2 fell to 100 s/h. Among the infants in the extended caffeine group, time spent below 90% SaO2 was 51 s/h at 35 weeks and 49 s/h at 36 weeks. However, there was no significant reduction in IH with extended caffeine use after 36 weeks.
The lack of effect of caffeine after 36 weeks PMA likely occurred because infants metabolize caffeine more quickly as they mature, so a higher dose would be required than is routinely required at younger ages in the NICU. Also, a critical but unresolved question is whether reducing the extent of intermittent hypoxia by extending caffeine treatment to term-equivalent age has any long-term benefits, such as improved neurodevelopment, or has any associated risks.
Phase 2 – Intermittent Hypoxia and Caffeine Levels
The second phase of the study was designed to sort out what the right dose of caffeine is to reduce the intermittent hypoxia we now know is still occurring after 36 weeks PMA. We are therefore now conducting a randomized trial of 2 different higher doses of caffeine at 9 NICUs. In addition to recording the intermittent Hypoxia, infant samples are being obtained to measure the caffeine levels present in the body.
Phase 3 – Impact of Intermittent Hypoxia
A study which is in the design phase will explore the problems that can result from this persisting intermittent hypoxia. We plan to use brain imaging (MRIs), measure various biomarkers of inflammatory and brain health, and obtain some assessment of genetic (epigenetic) modifications. There will be 10-15 NICU’s involved over a 2 year period.
Phase 4 – Long Term Consequences of Intermittent Hypoxia
Based on the results of this study in the planning phase, our long term goal will be to implement a definitive study to look at long term consequences of intermittent hypoxia and whether extended caffeine treatment will lead to better outcomes, including improved brain developmental. There are 40 hospitals that have committed to participate.